The five year research program proposed is focused on basic mechanisms of the genetic determination of obesity, a major health problem that is mediated by behavior. Human obesity has been shown to be under substantial genetic control. The precise mode of genetic inheritance is unknown, and there may be more than one form of genetic obesity. Moderate to extreme obesity is highly familial and may be influenced more strongly by genetic factors than less extreme levels of fatness. Pilot data indicate that both the population distribution and the familial pattern of fatness are consistent with major gene effects on moderate obesity. The proposed genetic study is unique in that it will focus on obesity (40% overweight) as well as on the whole range of human fatness (from fat to lean). Two sets of analyses will be performed. One set of analyses will focus on tests of major gene models for obesity, particularly for homogeneous subgroups of families. Genetic analyses will be conducted of body fatness data already collected on 844 randomly selected families and 1406 families selected through hyperlipidemic index cases from the Lipid Research Clinic Family Study. In this sample, all family members have measures of height, weight, blood chemistry and serum lipid levels. Index cases have these measures as well as reported height and weight at age 18. Analyses will assess whether there are different genetic mechanisms in homogeneous subgroups of families subdivided on the basis of characteristics of the index case, e.g., age at onset, and concomitant hyperlipidemia. A second set of analyses is aimed at identifying patient characteristics which can be used as markers for homogeneous subgroups for genetic studies. The analyses will focus on a separate sample of 450 obese patients to be added to an existing Obesity Research Center database over a three year period, including extensive patient information and family history of obesity for first degree relatives. Tests will be made of the relationship of familial risk for obesity to age at onset, fat distribution (upper vs lower body), response to treatment, metabolic rate, concomitant hyperlipidemia and fat cell number in obese patients. These two sets of related studies will help to identify genetic factors in obesity and target groups with high familial risk for treatment and prevention.